Triazole compounds and the use thereof

ABSTRACT

The present invention relates to triazole compounds of the following formula: where R 1 , R 2 , A, B and Ar have the meanings stated in the description. The compounds according to the invention have a high affinity for the dopamine D3 receptor and can therefore be used to treat disorders which respond to dopamine D 3  ligands.

The invention relates to triazole compounds and to the use of such compounds. Said compounds have valuable therapeutic properties and can be used to treat disorders which respond to dopamine D₃ receptor ligands.

Compounds which are of the type under discussion here and have physiological activity have been disclosed. U.S. Pat. Nos. 4,338,453, 4,408,049 and 4,577,020 describe triazole compounds which have antiallergic activity.

Neurons receive their information inter alia via G protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of them is dopamine.

Confirmed findings on the presence of dopamine and its physiological function as neurotransmitter have been published. Cells which respond to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other disorders are treated with drugs which interact with dopamine receptors.

By 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, namely D₁ and D₂ receptors.

Sokoloff et al., Nature 1990, 347: 146-151, found a third subtype, namely D₃ receptors. They are expressed mainly in the limbic system. The D₃ receptors differ structurally from the D₁ and D₂ receptors in about half the amino-acid residues.

The effect of neuroleptics has generally been ascribed to their affinity for D₂ receptors. Recent receptor-binding studies have confirmed this. According to these, most dopamine antagonists, like neuroleptics, have high affinity for D₂ receptors but only low affinity for D₃ receptors.

We have now found, surprisingly, that the compounds according to the invention have a high affinity for the dopamine D₃ receptor and only a low affinity for the D₂ receptor. They are thus selective D₃ ligands.

The present invention therefore relates to triazole compounds of the formula I: ##STR1## where A is a straight-chain or branched C₁ -C₁₈ -alkylene group which may comprise at least one group selected from O, S, NR³, CONR³, NR³ CO, COO, OCO, C₃ -C₆ -cycloalkylene or a double or triple bond, X is a radical of the formula: ##STR2## R¹ is H, CO₂ R³, NR³ R⁴, OR⁴, C₃ -C₆ -cycloalkyl or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen;

R² has the meanings indicated for R¹ or is CF₃, SR³, halogen or CN;

R³ is H or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl, phenyl or halogen;

R⁴ has the meanings indicated for R³ or is COR³ or CO₂ R³ ;

Ar is phenyl, pyridyl, pyrimidyl or triazinyl, where Ar may have from one to four substituents which are selected, independently of one another, from OR⁴, C₁ -C₈ -alkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, halogen, CN, CO₂ R³, NO₂, SO₂ R³, SO₃ R³, NR³ R⁴, SO₂ NR³ R⁴, SR³, CF₃, CHF₂, a 5- or 6-membered carbocyclic aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic aromatic or nonaromatic ring having 1 to 4 hetero atoms selected from O, S and N, where the carbocyclic or heterocyclic ring may be unsubstituted or substituted by C₁ -C₈ -alkyl, halogen, OC₁ -C₈ -alkyl, OH, NO₂ or CF₃ and where Ar may also be fused to a carbocyclic or heterocyclic ring of the type defined above, and the salts thereof with physiologically tolerated acids.

The compounds according to the invention are selective dopamine D₃ receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D₂ receptor, have fewer side effects than classical neuroleptics, which are D₂ receptor antagonists. The compounds can therefore be used to treat disorders which respond to dopamine D₃ receptor antagonists or agonists, eg. for treating disorders of the central nervous system, in particular schizophrenia, depression, neuroses and psychoses. They can additionally be used to treat sleep disorders and nausea and as antihistamines.

Within the scope of the present invention, the following terms have the meanings indicated below:

Alkyl (also in radicals such as alkoxy, alkyl-amino etc.) means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of one another, from OH and OC₁ -C₈ -alkyl.

Examples of an alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl etc.

Alkylene stands for straight-chain or branched radicals having, preferably, 2 to 15 carbon atoms, particularly preferably 3 to 10 carbon atoms.

The alkylene groups may comprise at least one of the abovementioned groups. This can--just like the double or triple bond mentioned--be arranged in the alkylene chain at any point or at the end of the chain so that it connects the chain to the triazole residue. The latter is preferred. When the alkylene group comprises a double or triple bond, it has at least three carbon atoms in the chain.

Halogen is F, Cl, Br, I and, in particular, Cl, Br, I.

R¹ and R² are preferably, independently of one another, H, C₁ -C₈ -alkyl, NR³ R⁴ or OR⁴.

Ar can have one, two, three or four substituents. They are preferably selected, independently of one another, from halogen, CF₃, CHF₂, NR³ R⁴, OR⁴, NO₂, C₁ -C₈ -alkyl, OC₁ -C₈ -alkyl, SR³ and CN, where R³ and R⁴ have the abovementioned meanings.

If one of the substituents of Ar is C₁ -C₈ -alkyl, a branched radical, in particular the isopropyl or t-butyl group, is preferred.

Ar preferably has at least one substituent and is, in particular, ##STR3## where D¹, D² and D³ are, independently of one another, CR or N, and R, X and Y are H or are the substituents of the radical Ar indicated above or below.

Ar is preferably unsubstituted or substituted phenyl, 2-, 3- or 4-pyridinyl or 2-, 4(6)- or 5-pyrimidyl.

When one of the substituents of the radical Ar is a 5- or 6-membered heterocyclic ring, examples thereof are a pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole or thiadiazole residue.

When one of the substituents of the radical Ar is a carbocyclic radical, it is, in particular, a phenyl, cyclopentyl or cyclohexyl radical.

When Ar is fused to a carbocyclic or heterocyclic radical, Ar is, in particular, a naphthalene, di- or tetrahydronaphthalene, quinoline, di- or tetrahydroquinoline, indole, dihydroindole, benzimidazole, benzothiazole, benzothiadiazole, benzopyrrole or benzotriazole residue.

X is preferably ##STR4##

A preferred embodiment comprises compounds of the formula I where A is C₃ -C₁₀ -alkylene which comprises at least one group which is selected from O, S, NR³, cyclohexylene, in particular 1,4-cyclohexylene, and a double or triple bond, where R³ is as defined above.

Another preferred embodiment comprises compounds of the formula I where

R¹ is H, OR⁴ where R⁴ is H or C₁ -C₈ -alkyl, or C₃ -C₆ -cycloalkyl or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen;

R² is H, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or NR³ R⁴ where R³ and R⁴ are, independently of one another, H, phenyl-C₁ -C₈ -alkyl or C₁ -C₈ -alkyl, or OR⁴ where R⁴ is H or C₁ -C₈ -alkyl, or CF₃ ;

A is as defined in claim 3, and

Ar is phenyl, pyridyl or pyrimidyl which may have one, two, three or four substituents which are selected from H, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or OR⁴ where R⁴ is H, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or CHF₂, CF₃, CN, Halogen, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, phenyl, naphthyl and a 5- or 6-membered heterocyclic aromatic radical with 1 to 3 hetero atoms selected from O, N and S.

Another preferred embodiment comprises compounds of the formula I where

R¹ is H or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen;

R² is H, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or NR³ R⁴ where R³ and R⁴ are, independently of one another, H or C₁ -C₈ -alkyl, or OR⁴ where R⁴ is H or C₁ -C₈ -alkyl, or CF₃ ;

A is C₁ -C₁₀ -alkylene which may comprise an oxygen or sulfur atom or the group NR³ where R³ is as defined above;

Ar is phenyl which may have one to four substituents which are selected, independently of one another, from H, CN, SR³, halogen, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or phenyl, naphthyl, OR⁴, NO₂, NR³ R⁴, CHF₂ and CF₃, where R³ and R⁴ have the stated meanings.

Particularly preferred in this connection are the compounds of the formula I where

A is SC₃ -C₁₀ -alkylene, OC₃ -C₁₀ -alkylene or NR³ -C₃ -C₁₀ -alkylene, where R³ is H or C₁ -C₈ -alkyl,

R¹ is H or C₁ -C₈ -alkyl;

R² has the abovementioned meanings;

X is: ##STR5## Ar is phenyl which has one to four substituents which are, independently of one another, H, C₁ -C₈ -alkyl, OC₁ -C₈ -alkyl, CHF₂, CF₃ or CN.

Ar has, in particular, two substituents which are located in positions 3 and 5, with one substituent being CF₃, CHF₂ or C₁ -C₈ -alkyl and the other substituent being H or C₁ -C₈ -alkyl.

Another preferred embodiment comprises compounds of the formula I where

Ar is pyrimidinyl which has one to three substituents which are selected, independently of one another, from H, C₁ -C₈ -alkyl, phenyl, naphthyl, C₃ -C₆ -cyclohexyl, OH, OC₁ -C₈ -alkyl, halogen, CN, CF₃, CHF₂ and a 5- or 6-membered heterocyclic aromatic radical with 1 to 3 hetero atoms selected from O, N and S;

R¹ is H or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen,

R² is H, NR³ R⁴ or OR⁴ where R³ and R⁴ are, independently of one another, H, C₁ -C₈ -alkyl or phenyl-C₁ -C₈ -alkyl;

A is C₁ -C₁₀ -alkylene which may comprise at least one group selected from O, S, NR³ where R³ is H or C₁ -C₈ -alkyl, and a double or triple bond; and

X is as defined above.

Another preferred embodiment comprises compounds of the formula I where

Ar is pyridinyl which has one to four substituents which are selected, independently of one another, from H, C₁ -C₈ -alkyl, phenyl, naphthyl, OH, OC₁ -C₈ -alkyl, halogen, CF₃, CN, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl and a 5- or 6-membered heterocyclic aromatic radical with 1 to 3 hetero atoms selected from O, N and S;

R¹ is H, C₁ -C₈ -alkyl, C₃ -C₆ -cycloalkyl or OR⁴ where R⁴ is H or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen; and

R², A and X are as defined above.

The invention also embraces the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung, Volume 10, pages 224 et seq., Birkhauser Verlag, Basle and Stuttgart, 1966.

The compounds of the formula I may have one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The invention also includes the tautomeric forms in each case.

The compounds of the formula I can be prepared by methods similar to conventional ones as described, for example, in Houben Weyl "Handbuch der Organishen Chemie", 4th Ed., Thieme Verlag, Stuttgart 1994, Volume E8/d, pages 479 et seq.; and A. R. Katritzky, C. W. Rees (ed.) "Comprehensive Heterocyclic Chemistry", 1st Ed. Pergamon Press 1984, in particular Vol. 5, part 4a, pages 733 et seq. and literature cited therein. The proess for preparing the compounds comprises i) reacting a compound of the general formula II: ##STR6## where Y¹ is a conventional leaving group, with a compound of the formula III

    H--X--Ar;

ii) to prepare a compound of the formula I where A is an oxygen or sulfur atom or NR³ :

a) reacting a compound of the formula IV: ##STR7## where Z¹ is O, S or NR³ and A¹ is C₀ -C₁₈ -alkylene, with a compound of the formula VI

    Y.sup.1 --A.sup.2 --X--Ar

where Y¹ has the abovementioned meanings, and A² is C₁ -C₁₈ -alkylene, where A¹ and A² together have 1 to 18 carbon atoms;

iii) to prepare a compound of the formula I where A comprises the group COO or CONR³ :

a) reacting a compound of the formula VII: ##STR8## where Y² is OH, OC₁ -C₄ -alkyl, Cl or, together with CO, is an activated carboxyl group, and A¹ has the abovementioned meanings, with a compound of the formula VIII:

    Z.sup.1 --A.sup.2 --X--Ar

where A² has the abovementioned meanings, and Z¹ is OH or NHR³,

iv) to prepare a compound of the formula I where A comprises the group OCO or NR³ CO:

a) reacting a compound of the formula IV ##STR9## where Z¹ is O or NR³, with a compound of the formula X:

    Y.sup.2 CO--A.sup.2 --X--Ar

where B and Y² have the abovementioned meanings, and where R¹, R², A, B and Ar have the abovementioned meanings.

The reactions described above generally take place in a solvent at from room temperature to the boiling point of the solvent used. Examples of solvents which can be used are ethyl acetate, tetrahydrofuran, dimethylformamide, dimethoxyethane, toluene, xylene or a ketone, such as acetone or methyl ethyl ketone.

An acid acceptor is present if required. Suitable acid acceptors are inorganic bases such as sodium or potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride or organic bases such as triethylamine or pyridine. The latter may also serve as solvents.

The crude product is isolated in a conventional way, for example by filtration, removal of the solvent by distillation or extraction from the reaction mixture. The resulting compound can be purified in a conventional way, for example by recrystallization from a solvent, chromatography or conversion into an acid addition compound.

The acid addition salts are prepared in a conventional way by mixing the free base with the appropriate acid, possibly in solution in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol, an ether such as methyl t-butyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate.

The abovementioned starting materials are disclosed in the literature or can be prepared by known processes.

To treat the abovementioned disorders, the compounds according to the invention are administered in a conventional manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is about 10 to 1000 mg per patient and day on oral administration and about 1 to 500 mg per patient and day on parenteral administration.

The invention also relates to pharmaceutical compositions which contain the compounds according to the invention. These compositions are in the usual solid or liquid pharmaceutical administration forms, for example as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. The active substances can in these cases be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain the active substance in an amount from 1 to 99% by weight.

The following examples serve to explain the invention without limiting it.

EXAMPLE 1 4-Methyl-3-[3-(4-{3-trifluoromethylphenyl}piperazinyl)propylmercapto]-4H-1,2,4-triazole ##STR10## a) 1-(3-Chloropropyl)-4-(3-trifluoromethylphenyl)piperazine

30 g (0.13 mol) of m-trifluoromethylphenylpiperazine, 23 g (0.146 mol) of 1,3-bromochloropropane [sic] and 15 g (0.148 mol) of triethylamine in 200 ml of THF were refluxed for 4 hours. Cooling was followed by filtration with suction and concentration. The viscous residue was taken up in ethyl acetate, washed with water, dried over MgSO₄ and then concentrated. The resulting residue comprised 39 g of product as yellowish oil (quantitative yield).

b) 4-Methyl-3-[3-(4-{3-trifluoromethylphenyl}piperazinyl)propylmercapto]-4H-1,2,4-triazole

1.15 g (10 mmol) of 3-mercapto-4-methyl-4H-1,2,4-triazole, 3.1 g (10.1 mmol) of 1-(3-chloropropyl)-4-(3-trifluoromethylphenyl)piperazine and 1.5 g (15 mmol) of triethylamine in 5 ml of DMF were stirred at 100° C. for 1 hour. The mixture was then poured into 5% strength hydrochloric acid and extracted with ethyl acetate. The aqueous phase was made alkaline with sodium hydroxide solution and then extracted again with ethyl acetate, and the organic phase was dried over MgSO₄ and concentrated. The residue was purified by chromatography (mobile phase: CH₂ Cl₂ /CH₃ OH=95/5). 2.1 g of product were obtained as a yellowish oil (=55% yield).

H-NMR [δ, ppm]: 2.02 (2H); 2.55 (2H); 2.61 (4H); 3.23 (6H); 3.33 (2H); 3.61 (3H); 7.06 (3H); 7.33 (1H); 8.12 (1H).

EXAMPLE 2 4-Methyl-3-[5-(4-{3-trifluoromethylphenyl}piperazinyl)-pentylmercapto]-4H-1,2,4-triazole ##STR11## a) 3-(5-Chloropentylmercapto)-4-methyl-4H-1,2,4-triazole

2.88 g (25 mmol) of 3-mercapto-4-methyl-4H-1,2,4-triazole, 4.64 g (25 mmol) of 1,5-bromochloropentane [sic] and 5.58 g (25.5 mmol) of triethylamine in 100 ml of THF were refluxed for 4 hours. Cooling was followed by filtration with suction, concentration and purification of the residue by chromatography (mobile phase: CH₂ Cl₂ /CH₃ OH=95/5). 1.9 g of product were obtained (=35% yield).

b) 4-Methyl-3-[5-(4-{3-trifluoromethylphenyl}piperazinyl)pentylmercapto]-4H-1,2,4-triazole

1.9 g (8.66 mmol) of product from 2a), 2.19 g (9.52 mmol) of m-trifluoromethylphenylpiperazine and 0.96 g (9.52 mmol) of triethylamine in 5 ml of DMF were stirred at 90° C. for 5 hours. The mixture was then poured into water and extracted three times with CH₂ Cl₂, and the organic phase was dried over MgSO₄ and concentrated. The residue was mixed with methyl t-butyl ether and filtered with suction, and the mother liquor was concentrated. Purification by chromatography (mobile phase: CH₂ Cl₂ /CH₃ OH=95/5) resulted in 2.1 g of product (=59% yield).

Melting point 70-76° C.

The following compounds were prepared in a similar way:

    __________________________________________________________________________                                      Physical data, H-NMR                                                           [δ, ppm]                                No.                                                                               Example                       melting point [° C.]                   __________________________________________________________________________         ##STR12##                    1.83(2H); 2.45(6H); 3.0(2H);  3.27(4H);                                        6.0(2H); 7.05(1H);  7.15(1H); 7.2(1H);                                         7.4(1H);  11.95(1H)                           4                                                                                  ##STR13##                    1.85(2H); 2.3(3H); 2.45(2H);  2.5(4H);                                         3.1(2H); 3.2(4H);  5.8(2H); 7.05(1H);                                          7.15(1H);  7.2(1H); 7.4(1H)                   5                                                                                  ##STR14##                    2.1(2H); 2.7(6H); 3.22(2H);  3.42(4H);                                         7.1(3H); 7.38(1H);  7.92(1H)                  6                                                                                  ##STR15##                    200-205                                       7                                                                                  ##STR16##                    2.05(2H); 2.55(2H); 2.6(4H);  3.23(4H);                                        3.4(2H); 3.65(3H);  7.08(3H); 7.35(1H)        8                                                                                  ##STR17##                    2.0(2H); 2.53(2H); 2.6(4H);  3.13(2H);                                         3.25(7H); 7.08(3H);  7.35(1H); 9.88(1H)       9                                                                                  ##STR18##                    1.5(6H); 1.98(2H); 2.55(2H);  2.62(4H);                                        3.15(2H); 3.22(4H);  4.32(1H); 7.08(3H);                                       7.35(1H);  10.0(1H)                           10                                                                                 ##STR19##                    1.95(2H); 2.5(2H); 2.58(4H);  3.1(2H);                                         3.22(4H); 3.4(3H);  4.4(2H); 7.08(3H);                                         7.35(1H)                                      11                                                                                 ##STR20##                    2.52(4H); 3.0(2H); 3.22(4H);  3.4(3H);                                         3.64(2H); 4.96(2H);  5.62(1H); 5.72(1H);                                       7.05(3H);  7.3(1H)                            12                                                                                 ##STR21##                    1.95(2H); 2.52(2H); 2.6(4H);  3.12(2H);                                        3.22(4H); 3.4(3H);  4.2(2H); 6.6(1H);                                          7.0(3H);  7.35(1H)                            13                                                                                 ##STR22##                    1.15(6H); 1.75(2H);  2.45(10H); 2.9(2H);                                       3.08(4H);  3.3(3H); 5.95(2H); 6.45(1H);                                        6.55(2H)                                      14                                                                                 ##STR23##                    166-171                                       15                                                                                 ##STR24##                    1.25(18H); 1,75 (2H);  2.4(2H);                                                2.45(4H); 2.9(2H);  3.1(4H); 3.35(3H);                                         5.95(2H);  6.75(2H); 6.88(1H)                 __________________________________________________________________________

The compounds according to the invention which compiled in Tables 1 to 3 below were obtained in a similar manner.

The compounds compiled in Tables 4 to 8 below can likewise be obtained in a similar manner.

                                      TABLE 1                                      __________________________________________________________________________      ##STR25##                                                                     Example No.                                                                          R.sup.1                                                                             R.sup.2                                                                            R.sup.6                                                                            X-Y  A.sub.1                                                                          A.sub.2                                              __________________________________________________________________________     16    CH.sub.3                                                                            NH.sub.2                                                                           i Prop                                                                             CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                17    CH.sub.3                                                                            NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.2 CH═CH(CH.sub.2).sub.2                                   --                                                   18    CH.sub.3                                                                            NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.2 --                                19    CH.sub.3                                                                            NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S --CH.sub.2 C(CH.sub.3)═CHCH.sub.2 --             20    CH.sub.3 CH.sub.2                                                                   NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                21    CH.sub.3                                                                            NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S                                                                                 ##STR26##                                           22    n Prop                                                                              NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                23    i Prop                                                                              NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                24    CH.sub.3 CH.sub.2                                                                   NH.sub.2                                                                           CHF.sub.2                                                                          CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                25    n Prop                                                                              NH.sub.2                                                                           CHF.sub.2                                                                          CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                26    CH.sub.3 CH.sub.2                                                                   NH.sub.2                                                                           i Prop                                                                             CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                27    n Prop                                                                              NH.sub.2                                                                           i Prop                                                                             CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                28    i Prop                                                                              NH.sub.2                                                                           i Prop                                                                             CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                29    CH.sub.3                                                                            NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.7 --                                30    CH.sub.3                                                                            NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.8 --                                31    CH.sub.3                                                                            NH.sub.2                                                                           i Prop                                                                             CH.sub.2 --N                                                                        S --(CH.sub.2).sub.9                                   32    CH.sub.3                                                                            NH.sub.2                                                                           CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.4 O(CH.sub.2).sub.4 --              33    CH.sub.3                                                                            NH.sub.2                                                                           i Prop                                                                             CH.sub.2 --N                                                                        S --(CH.sub.2).sub.4 O(CH.sub.2).sub.4 --              34    CH.sub.3                                                                            NHCH.sub.3                                                                         CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                35    CH.sub.3                                                                            NH.sub.2                                                                           i Prop                                                                             CH.sub.2 --N                                                                        S --CH.sub.2 C(CH.sub.3)═CHCH.sub.2 --             36    CH.sub.3                                                                            NH.sub.2                                                                           CF.sub.3                                                                           CH═N                                                                            S --(CH.sub.2).sub.3 --                                37    CH.sub.3                                                                            NHCH.sub.3                                                                         CHF.sub.2                                                                          CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                                __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________      ##STR27##                                                                     Example No.                                                                          R.sup.1                                                                           R.sup.2                                                                           R.sup.6                                                                             D   R.sup.8                                                                            X-Y  A.sub.1                                                                          A.sub.2                                        __________________________________________________________________________     38    CH.sub.3                                                                          NH.sub.2                                                                          CF.sub.3                                                                            CH  H   CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                          39    CH.sub.3                                                                          NH.sub.2                                                                          Cl   CH  CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                          40    CH.sub.3                                                                          NH.sub.2                                                                          t But                                                                               N   CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                          41    CH.sub.3                                                                          NH.sub.2                                                                          1-Pyrrolyl                                                                          N   CH.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                          42    CH.sub.3                                                                          NH.sub.2                                                                          t But                                                                               N   CF.sub.3                                                                           CH.sub.2 --N                                                                        S --CH.sub.2 C(CH.sub.3)═CHCH.sub.2 --       43    CH.sub.3                                                                          NH.sub.2                                                                          t But                                                                               N   CF.sub.3                                                                           CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                          44    CH.sub.3                                                                          NH.sub.2                                                                          t But                                                                               N   t But                                                                              CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --                          45    CH.sub.3                                                                          NH.sub.2                                                                          i Prop                                                                              C--CN                                                                              i Prop                                                                             CH.sub.2 --N                                                                        S --(CH.sub.2).sub.3 --.                         __________________________________________________________________________

                  TABLE 3                                                          ______________________________________                                         Physical data of the compounds of Examples 16-45                               Example No.                                                                              Mp. ° C.                                                                             .sup.1 H-NMR                                            ______________________________________                                         16                     1.2 (6H); 1.9 (2H); 2.5                                                        (6H); 2.8 (1H); 3.2 (6H);                                                      3.5 (3H); 4.4 (2H); 6.7                                                        (3H); 7.1 (1H)                                          17        194-196°                                                                Dihydrochloride                                                      18        109-110°                                                                Hydrochloride                                                        19        132-134°                                                      20                     1.3 (3H); 2.0 (2H); 2.5                                                        (6H); 3.2 (6H); 3.8 (2H; 4.6                                                   (2H); 7.0 (3H); 7.4 (1H)                                21        154-155°                                                      22                     1.0 (3H); 1.8 (2H); 2.0                                                        (2H); 2.5 (6H); 3.1 (6H);                                                      3.7 (2H); 4.4 (2H); 7.0                                                        (3H); 7.3 (1H)                                          23                     1.2 (6H); 2.0 (2H): 2.3                                                        (6H); 3.1 (6H); 4.1 (2H);                                                      4.3 (1H); 7.0 (3H); 7.2 (1H)                            24                     1.2 (3H); 1.8 (2H); 2.4 (2H)                                                   2.5 (4H); 2.9 (2H); 3.1                                                        (4H); 3.8 (2H); 6.0 (2H);                                                      6.9 (1H); 7.0 (3H), 7.3 (1H)                            25                     1.0 (3H); 1.7 (2H); 2.0                                                        (2H); 2.5 (2H); 2.6 (4H);                                                      3.0 (6H), 3.7 (2H), 4.6                                                        (2H); 6.6 (1H); 7.0 (3H);                                                      7.4 (1H)                                                26                     1.2 (9H); 1.9 (2H); 2.5                                                        (2H); 2.6 (4H); 2.9 (1H);                                                      3.15 (6H); 3.8 (2H); 6.8                                                       (3H); 7.2 (1H)                                          27                     0.9 (3H); 1.2 (6H), 1.7                                                        (2H); 1.9 (2H); 2.5 (2H);                                                      2.6 (4H); 2.8 (1H); 2.9                                                        (2H); 3.2 (4H); 3.4 (2H);                                                      6.8 (3H); 7.3 (1H)                                      28                     1.2 (6H); 1.5 (6H); 1.9                                                        (2H); 2.4 (2H); 2.5 (4H);                                                      2.8 (1H); 3.2 (6H), 4.3                                                        (3H); 6.75 (3H), 7.15 (1H)                              29        118-119°                                                      30        164-166°                                                                Fumarate                                                             31                     1.2 (6H); 1.4 (14H), 1.7                                                       (2H); 2.4 (2H), 2.6 (4H),                                                      2.8 (1H); 3.0 (2H); 3.2                                                        (4H), 3.4 (3H), 4.6 (2H),                                                      6.8 (3H); 7.2 (1H)                                      32                     1.7 (8H); 2.4 (2H); 2.6                                                        (4H); 3.0 (2H; 3.3 (4H); 3.5                                                   (7H); 4.8 (2H); 7.1 (3H);                                                      7.3 (1H)                                                33                     1.2 (6H); 1.6 (8H); 2.4                                                        (2H); K 2.6 (4H); 2.9                                                          (1H); 3.1 (2H); 3.2 (4H); 3.3                                                  (7H); 4.8 (2H); 6.8 (3H);                                                      7.2 (1H)                                                34        234-270°                                                                Trihydrochloride                                                     35        126-129°                                                      36         93-100°                                                      37        234-235°                                                                Dihydrochoride                                                       38        153-155°                                                      39        116-118°                                                      40         51-60°                                                       41         65-67°                                                       42         67-72°                                                       43        121-126°                                                      44        180-183°                                                                Fumarate                                                             45        130-133°                                                      ______________________________________                                    

                                      TABLE 4                                      __________________________________________________________________________      ##STR28##                                                                     Example No.                                                                          R1 R2  R5  R6  R7  R8   R9 X-Y  A.sub.1                                                                             A.sub.2                             __________________________________________________________________________     46    CH.sub.3                                                                          NH.sub.2                                                                           H   tBut                                                                               H   Me   H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               47    CH.sub.3                                                                          NH.sub.2                                                                           H   tBut                                                                               H   Ph   H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               48    CH.sub.3                                                                          NH.sub.2                                                                           H   tBut                                                                               H   1-Pyrrolyl                                                                          H  CH.sub.2 --N                                                                        NH   --(CH.sub.2).sub.3 --               49    CH.sub.3                                                                          NH.sub.2                                                                           H   iProp                                                                              H   2-Napht                                                                             H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --               50    CH.sub.3                                                                          NH.sub.2                                                                           H   Et  H   tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               51    CH.sub.3                                                                          NH.sub.2                                                                           OMe tBut                                                                               H   H    H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --               52    CH.sub.3                                                                          NH.sub.2                                                                           OMe CF.sub.3                                                                           H   H    H  CH═C                                                                            S    --(CH.sub.2).sub.3 --               53    CH.sub.3                                                                          NH.sub.2                                                                           H   CF.sub.3                                                                           H   tBut H  CH.sub.2 --N                                                                        NH   --(CH.sub.2).sub.3 --               54    CH.sub.3                                                                          NH.sub.2                                                                           OiProp                                                                             iProp                                                                              H   H    H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               55    CH.sub.3                                                                          NH.sub.2                                                                           H   H   CN  tBut H  CH.sub.2 --N                                                                        O    --(CH.sub.2).sub.3 --               56    CH.sub.3                                                                          NH.sub.2                                                                           H   H   F   tBut H  CH═C                                                                            S    --(CH.sub.2).sub.3 --               57    CH.sub.3                                                                          NH.sub.2                                                                           H   H   Cl  iProp                                                                               H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --               58    CH.sub.3                                                                          NH.sub.2                                                                           H   tBut                                                                               H   H    OMe                                                                               CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               59    CH.sub.3                                                                          NH.sub.2                                                                           OMe tBut                                                                               H   tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               60    CH.sub.3                                                                          NH.sub.2                                                                           OMe tBut                                                                               H   CF.sub.3                                                                            H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               61    CH.sub.3                                                                          NH.sub.2                                                                           OMe CF.sub.3                                                                           H   tBut H  CH.sub.2 --N                                                                        NH   --(CH.sub.2).sub.3 --               62    CH.sub.3                                                                          NH.sub.2                                                                           H   nProp                                                                              CN  tBut H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --               63    CH.sub.3                                                                          NH.sub.2                                                                           H   CF.sub.3                                                                           CN  iProp                                                                               H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               64    CH.sub.3                                                                          NH.sub.2                                                                           H   Ph  C.tbd.CH                                                                           tBut H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --               65    CH.sub.3                                                                          NH.sub.2                                                                           OMe tBut                                                                               CN  H    H  CH═C                                                                            S    --(CH.sub.2).sub.3 --               66    CH.sub.3                                                                          NH.sub.2                                                                           H   tBut                                                                               CN  CF.sub.3                                                                            OMe                                                                               CH.sub.2 --N                                                                        NH   --(CH.sub.2).sub.3 --               67    CH.sub.3                                                                          NH.sub.2                                                                           OMe nProp                                                                              F   tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               68    CH.sub.3                                                                          NH.sub.2                                                                           H   Ph  CN  tBut Me CH.sub.2 --N                                                                        O    --(CH.sub.2).sub.3 --               69    CH.sub.3                                                                          NH.sub.2                                                                           OMe tBut                                                                               F   H    H  CH═C                                                                            S    --(CH.sub.2).sub.3 --               70    CH.sub.3                                                                          NH.sub.2                                                                           H   iProp                                                                              H   H    OMe                                                                               CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               71    iProp                                                                             NH.sub.2                                                                           H   tBut                                                                               H   Me   H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               72    iProp                                                                             NH.sub.2                                                                           H   tBut                                                                               H   Ph   H  CH.sub.2 --N                                                                        NH   --(CH.sub.2).sub.4 --               73    iProp                                                                             NH.sub.2                                                                           H   tBut                                                                               H   1-Pyrrolyl                                                                          H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --               74    iProp                                                                             NH.sub.2                                                                           H   iProp                                                                              H   2-Napht                                                                             H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --               75    iProp                                                                             NH.sub.2                                                                           H   Et  H   tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.5 --               76    iProp                                                                             NH.sub.2                                                                           OMe tBut                                                                               H   H    H  CH.sub.2 --N                                                                        O    --(CH.sub.2).sub.5 --               77    iProp                                                                             NH.sub.2                                                                           OMe CF.sub.3                                                                           H   H    H  CH═C                                                                            NH   --(CH.sub.2).sub.4 --               78    iProp                                                                             NH.sub.2                                                                           H   CF.sub.3                                                                           H   tBut H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.4 --               79    iProp                                                                             NH.sub.2                                                                           OiProp                                                                             iProp                                                                              H   H    H  CH═C                                                                            S    --(CH.sub.2).sub.3 --               80    iProp                                                                             NH.sub.2                                                                           H   H   CN  tBut H  CH.sub.2 --N                                                                        NH   --(CH.sub.2).sub.3 --               81    iProp                                                                             NH.sub.2                                                                           H   H   F   tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               82    iProp                                                                             NH.sub.2                                                                           H   H   Cl  iProp                                                                               H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --               83    iProp                                                                             NH.sub.2                                                                           H   tBut                                                                               H   H    OMe                                                                               CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               84    iProp                                                                             NH.sub.2                                                                           OMe tBut                                                                               H   tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --               85    iProp                                                                             NH.sub.2                                                                           OMe tBut                                                                               H   CF.sub.3                                                                            H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               86    iProp                                                                             NH.sub.2                                                                           OMe CF.sub.3                                                                           H   tBut H  CH.sub.2 --N                                                                        NH   --(CH.sub.2).sub.5 --               87    iProp                                                                             NH.sub.2                                                                           H   nProp                                                                              CN  tBut H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --               88    iProp                                                                             NH.sub.2                                                                           H   CF.sub.3                                                                           CN  iProp                                                                               H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --               89    iProp                                                                             NH.sub.2                                                                           H   Ph  C.tbd.CH                                                                           tBut H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --               90    iProp                                                                             NH.sub.2                                                                           OMe tBut                                                                               CN  H    H  CH═C                                                                            S    --(CH.sub.2).sub.6 --               91    iProp                                                                             NH.sub.2                                                                           H   tBut                                                                               CN  CF.sub.3                                                                            OMe                                                                               CH.sub.2 --N                                                                        NH   --(CH.sub.2).sub.3 --               92    iProp                                                                             NH.sub.2                                                                           OMe nProp                                                                              F   tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.5 --               93    iProp                                                                             NH.sub.2                                                                           H   Ph  CN  tBut Me CH.sub.2 --N                                                                        O    --(CH.sub.2).sub.3 --               94    iProp                                                                             NH.sub.2                                                                           OMe tBut                                                                               F   H    H  CH═C                                                                            S    --(CH.sub.2).sub.4 --               95    iProp                                                                             NH.sub.2                                                                           H   iProp                                                                              H   H    OMe                                                                               CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --               96    iProp                                                                             NHMe                                                                               H   tBut                                                                               H   Me   H  CH.sub.2 --N                                                                        S    --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                97    iProp                                                                             NHMe                                                                               H   tBut                                                                               H   Ph   H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                98    iProp                                                                             NHMe                                                                               H   tBut                                                                               H   1-Pyrrolyl                                                                          H  CH.sub.2 --N                                                                        S    --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                99    iProp                                                                             NHMe                                                                               H   iProp                                                                              H   2-Napht                                                                             H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       100   iProp                                                                             NHMe                                                                               H   Et  H   tBut H  CH.sub.2 --N                                                                        S    --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       101   iProp                                                                             OH  OMe tBut                                                                               H   H    H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       102   iProp                                                                             OH  OMe CF.sub.3                                                                           H   H    H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       103   iProp                                                                             OH  H   CF.sub.3                                                                           H   tBut H  CH.sub.2 --N                                                                        S    --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                104   iProp                                                                             OH  OiProp                                                                             iProp                                                                              H   H    H  CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                105   iProp                                                                             OMe H   H   CN  tBut H  CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                106   iProp                                                                             OMe H   H   F   tBut H  CH═C                                                                            S    --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       107   iProp                                                                             OMe H   H   Cl  iProp                                                                               H  CH═C                                                                            O    --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       108   iProp                                                                             OMe H   tBut                                                                               H   H    OMe                                                                               CH═C                                                                            NH   --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       109   iProp                                                                             NHMe                                                                               OMe tBut                                                                               H   tBut H  CH.sub.2 --N                                                                        S    --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                110   iProp                                                                             NHMe                                                                               OMe tBut                                                                               H   CF.sub.3                                                                            H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                111   iProp                                                                             NHMe                                                                               OMe CF.sub.3                                                                           H   tBut H  CH.sub.2 --N                                                                        S    --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                112   iProp                                                                             NHMe                                                                               H   nProp                                                                              CN  tBut H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       113   iProp                                                                             NHMe                                                                               H   CF.sub.3                                                                           CN  iProp                                                                               H  CH.sub.2 --N                                                                        S    --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       114   iProp                                                                             OH  H   Ph  C.tbd.CH                                                                           tBut H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       115   iProp                                                                             OH  OMe tBut                                                                               CN  H    H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       116   iProp                                                                             OH  H   tBut                                                                               CN  CF.sub.3                                                                            OMe                                                                               CH.sub.2 --N                                                                        S    --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                117   iProp                                                                             OH  OMe nProp                                                                              F   tBut H  CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                118   iProp                                                                             OMe H   Ph  CN  tBut Me CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --CH═CH--CH.sub.                                                2 --                                119   iProp                                                                             OMe OMe tBut                                                                               F   H    H  CH═C                                                                            S    --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       120   iProp                                                                             OMe H   iProp                                                                              H   H    OMe                                                                               CH═C                                                                            S    --CH.sub.2 --C(CH.sub.3)═CH                                                --CH.sub.2 --                       __________________________________________________________________________

                                      TABLE 5                                      __________________________________________________________________________      ##STR29##                                                                     Example No.                                                                          R1 R2   R6  R8   R9  X-Y  A.sub.1                                                                             A.sub.2                                   __________________________________________________________________________     121   CH.sub.3                                                                          NH.sub.2                                                                            tBut                                                                               Ph   H   CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                     122   CH.sub.3                                                                          NH.sub.2                                                                            tBut                                                                               2-Napht                                                                             H   CH.sub.2 --N                                                                        S    --CH.sub.2 --C(CH.sub.3)═CH--CH.s                                          ub.2 --                                   123   CH.sub.3                                                                          NH.sub.2                                                                            tBut                                                                               1-Pyrrolyl                                                                          H   CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                     124   CH.sub.3                                                                          NHMe tBut                                                                               cHex H   CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                     125   CH.sub.3                                                                          NH.sub.2                                                                            tBut                                                                               nHex H   CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.5 --                     126   CH.sub.3                                                                          NH.sub.2                                                                            tBut                                                                               H    OMe CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                     127   CH.sub.3                                                                          NHMe iProp                                                                              H    OMe CH.sub.2 --N                                                                        S    --CH.sub.2 --C(CH.sub.3)═CH--CH.s                                          ub.2 --                                   128   CH.sub.3                                                                          NH.sub.2                                                                            H   CH.sub.3                                                                            OMe CH═C                                                                            NH   --(CH.sub.2).sub.3 --                     129   CH.sub.3                                                                          NH.sub.2                                                                            H   iProp                                                                               OMe CH.sub.2 --N                                                                        O    --CH.sub.2 --CH═CH--CH.sub.2 --       130   CH.sub.3                                                                          NH.sub.2                                                                            tBut                                                                               tBut OMe CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                     131   CH.sub.3                                                                          NHMe tBut                                                                               iProp                                                                               OMe CH.sub.2 --N                                                                        S    --CH.sub.2 --C(CH.sub.3)═CH--CH.s                                          ub.2 --                                   132   CH.sub.3                                                                          NH.sub.2                                                                            Ph  tBut Cl  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                     133   CH.sub.3                                                                          NH.sub.2                                                                            2-Napht                                                                            tBut Me  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                     134   CH.sub.3                                                                          NH.sub.2                                                                            tBut                                                                               CF.sub.3                                                                            OMe CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                     135   CH.sub.3                                                                          NH.sub.2                                                                            tBut                                                                               H    CH.sub.3                                                                           CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                     136   iProp                                                                             NH.sub.2                                                                            tBut                                                                               Ph   H   CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                     137   iProp                                                                             NH.sub.2                                                                            tBut                                                                               2-Napht                                                                             H   CH═C                                                                            NH   --(CH.sub.2).sub.3 --                     138   iProp                                                                             NH.sub.2                                                                            tBut                                                                               1-Pyrrolyl                                                                          H   CH.sub.2 --N                                                                        O    --CH.sub.2 --C(CH.sub.3)═CH--CH.s                                          ub.2 --                                   139   iProp                                                                             NH.sub.2                                                                            tBut                                                                               cHex H   CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                     140   iProp                                                                             OH   tBut                                                                               nHex H   CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                     141   nProp                                                                             OH   tBut                                                                               H    OMe CH═C                                                                            S    --(CH.sub.2).sub.4 --                     142   nProp                                                                             OMe  iProp                                                                              H    OMe CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --CH.sub.2 --CH═CH--CH.sub.2 --       143   nProp                                                                             OMe  H   CH.sub.3                                                                            OMe CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                     144   nProp                                                                             NCH.sub.2 Ph                                                                        H   iProp                                                                               OMe CH.sub.2 --N                                                                        S    --CH.sub.2 --C(CH.sub.3)═CH--CH.s                                          ub.2 --                                   145   iProp                                                                             OH   tBut                                                                               tBut OMe CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.4 --                     146   iProp                                                                             OH   tBut                                                                               iProp                                                                               OMe CH.sub.2 --N                                                                        S    --CH.sub.2 --CH═CH--CH.sub.2 --       147   iProp                                                                             OMe  Ph  tBut Cl  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.5 --                     148   nProp                                                                             OMe  2-Napht                                                                            tBut Me  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                     149   nProp                                                                             NCH.sub.2 Ph                                                                        tBut                                                                               CF.sub.3                                                                            OMe CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                     150   nProp                                                                             NHMe tBut                                                                               H    CH.sub.3                                                                           CH═C                                                                            S    --(CH.sub.2).sub.3 --                     __________________________________________________________________________

                                      TABLE 6                                      __________________________________________________________________________      ##STR30##                                                                     Example No.                                                                          R1 R2  R5 R7 R8 R9 X--Y A1   A2                                          __________________________________________________________________________     151   CH.sub.3                                                                          NH.sub.2                                                                           OMe                                                                               H  tBut                                                                              H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                       152   CH.sub.3                                                                          OH  OMe                                                                               H  CF.sub.3                                                                          H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                       153   iProp                                                                             NHMe                                                                               OMe                                                                               H  tBut                                                                              H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2 --         154   CH.sub.3                                                                          NH.sub.2                                                                           H  CN tBut                                                                              H  CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --C(CH.sub.3)═CH--CH.sub                                        .2 --                                       155   CH.sub.3                                                                          NHMe                                                                               H  F  tBut                                                                              H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                       156   cProp                                                                             NH.sub.2                                                                           Me Cl iProp                                                                             H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                       157   CH.sub.3                                                                          NHMe                                                                               H  H  iProp                                                                             OMe                                                                               CH═C                                                                            S    --(CH.sub.2).sub.3 --                       158   CH.sub.3                                                                          NH.sub.2                                                                           H  H  tBut                                                                              OMe                                                                               CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2 --         159   iProp                                                                             NH.sub.2                                                                           CN H  CF.sub.3                                                                          H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                       160   OH NHMe                                                                               H  CN H  OMe                                                                               CH.sub.2 --N                                                                        O    --(CH.sub.2).sub.3 --                       161   CH.sub.3                                                                          OH  H  H  tBu                                                                               OEt                                                                               CH═C                                                                            S    --CH.sub.2 --C(CH.sub.3)═CH--CH.sub                                        .2 --                                       162   Et NH.sub.2                                                                           H  CN tBut                                                                              H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                       163   CH.sub.3                                                                          NH.sub.2                                                                           Me H  iProp                                                                             H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                       164   iProp                                                                             NH.sub.2                                                                           OMe                                                                               CN tBut                                                                              H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                       165   CH.sub.3                                                                          NH.sub.2                                                                           OMe                                                                               Me tBut                                                                              H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                       166   CH.sub.3                                                                          NHMe                                                                               H  CN tBut                                                                              OMe                                                                               CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2 --         167   CH.sub.3                                                                          NH.sub.2                                                                           Me H  tBut                                                                              OMe                                                                               CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --C(CH.sub.3)═CH--CH.sub                                        .2 --                                       168   iProp                                                                             NH.sub.2                                                                           H  Cl CF.sub.3                                                                          Me CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.5 --                       169   OH NHMe                                                                               OMe                                                                               CN tBut                                                                              Me CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                       170   CH.sub.3                                                                          OH  Me Me iProp                                                                             Me CH═C                                                                            S    --(CH.sub.2).sub.4 --                       171   CH.sub.3                                                                          OH  OMe                                                                               H  iProp                                                                             H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                       __________________________________________________________________________

                                      TABLE 7                                      __________________________________________________________________________      ##STR31##                                                                     Example No.                                                                          R1 R2  R5 R6  R8   R9 X--Y A1   A2                                       __________________________________________________________________________     172   CH.sub.3                                                                          NH.sub.2                                                                           H  tBut                                                                               tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                    173   CH.sub.3                                                                          OH  H  tBut                                                                               Ph   H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                    174   iProp                                                                             NHMe                                                                               H  tBut                                                                               1-Pyrrolyl                                                                          H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2                                               --                                       175   CH.sub.3                                                                          NH.sub.2                                                                           H  nPropyl                                                                            tBut H  CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --C(CH.sub.3)═CH--CH.                                           sub.2 --                                 176   CH.sub.3                                                                          NHMe                                                                               H  CF.sub.3                                                                           tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                    177   cProp                                                                             NH.sub.2                                                                           H  2-Napht                                                                            tBut H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                    178   CH.sub.3                                                                          NHMe                                                                               OMe                                                                               tBut                                                                               H    H  CH═C                                                                            S    --(CH.sub.2).sub.3 --                    179   CH.sub.3                                                                          NH.sub.2                                                                           OMe                                                                               iProp                                                                              H    H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2                                               --                                       180   iProp                                                                             NH.sub.2                                                                           OMe                                                                               H   CF.sub.3                                                                            H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                    181   OH NHMe                                                                               H  tBut                                                                               H    OMe                                                                               CH.sub.2 --N                                                                        O    --(CH.sub.2).sub.3 --                    182   CH.sub.3                                                                          OH  H  iProp                                                                              H    Me CH═C                                                                            S    --CH.sub.2 --C(CH.sub.3)═CH--CH.                                           sub.2 --                                 183   Et NH.sub.2                                                                           CN tBut                                                                               H    H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                    184   CH.sub.3                                                                          NH.sub.2                                                                           H  H   CF.sub.3                                                                            Me CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                    185   OH NHMe                                                                               OMe                                                                               tBut                                                                               iProp                                                                               H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                    186   CH.sub.3                                                                          OH  OMe                                                                               CF.sub.3                                                                           tBut H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2                                               --                                       187   Et NH.sub.2                                                                           Me tBut                                                                               nProp                                                                               H  CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --C(CH.sub.3)═CH--CH.                                           sub.2 --                                 188   CH.sub.3                                                                          NH.sub.2                                                                           Me tBut                                                                               H    OMe                                                                               CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.5 --                    189   CH.sub.3                                                                          NH.sub.2                                                                           OMe                                                                               tBut                                                                               tBut OMe                                                                               CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                    190   iProp                                                                             NH.sub.2                                                                           Me CF.sub.3                                                                           tBut OMe                                                                               CH═C                                                                            S    --(CH.sub.2).sub.4 --                    191   CH.sub.3                                                                          OH  H  nProp                                                                              tBut H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                    __________________________________________________________________________

                                      TABLE 8                                      __________________________________________________________________________      ##STR32##                                                                     Example No.                                                                          R1 R2  R6 R7  R8 R9 X--Y A1   A2                                         __________________________________________________________________________     192   CH.sub.3                                                                          NH.sub.2                                                                           tBut                                                                              H   tBut                                                                              H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                      193   CH.sub.3                                                                          OH  tBut                                                                              CN  H  H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                      194   iProp                                                                             NHMe                                                                               tBut                                                                              H   H  OMe                                                                               CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2 --        195   CH.sub.3                                                                          NH.sub.2                                                                           H  CN  tBu                                                                               H  CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --C(CH.sub.3)═CH--CH.su                                         b.2 --                                     196   CH.sub.3                                                                          NHMe                                                                               CF.sub.3                                                                          H   tBut                                                                              H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                      197   cProp                                                                             NH.sub.2                                                                           nProp                                                                             H   iProp                                                                             H  CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                      198   CH.sub.3                                                                          NHMe                                                                               H  H   iProp                                                                             OMe                                                                               CH═C                                                                            S    --(CH.sub.2).sub.3 --                      199   CH.sub.3                                                                          NH.sub.2                                                                           tBut                                                                              H   tBut                                                                              H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2 --        200   iProp                                                                             NH.sub.2                                                                           tBut                                                                              CN  H  H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                      201   OH NHMe                                                                               tBut                                                                              H   H  OMe                                                                               CH.sub.2 --N                                                                        O    --(CH.sub.2).sub.3 --                      202   CH.sub.3                                                                          OH  H  CN  tBu                                                                               H  CH═C                                                                            S    --CH.sub.2 --C(CH.sub.3)═CH--CH.su                                         b.2 --                                     203   Et NH.sub.2                                                                           CF.sub.3                                                                          H   tBut                                                                              H  CH.sub.2 --N                                                                        --CH.sub.2 --                                                                       --(CH.sub.2).sub.3 --                      204   CH.sub.3                                                                          NH.sub.2                                                                           nProp                                                                             H   iProp                                                                             H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                      205   CH.sub.3                                                                          NH.sub.2                                                                           nProp                                                                             CN  tBut                                                                              H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                      206   CH.sub.3                                                                          OH  CF.sub.3                                                                          CN  iProp                                                                             H  CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                      207   iProp                                                                             NHMe                                                                               Ph C═CH                                                                           tBut                                                                              H  CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2 --        208   CH.sub.3                                                                          NH.sub.2                                                                           tBut                                                                              CN  tBut                                                                              H  CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --C(CH.sub.3)═CH--CH.su                                         b.2 --                                     209   CH.sub.3                                                                          NHMe                                                                               tBut                                                                              H   nProp                                                                             OMe                                                                               CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                      210   cProp                                                                             NH.sub.2                                                                           Ph H   tBut                                                                              OMe                                                                               CH═C                                                                            --CH.sub.2 --                                                                       --(CH.sub.2).sub.5 --                      211   CH.sub.3                                                                          NHMe                                                                               CF.sub.3                                                                          H   tBut                                                                              OMe                                                                               CH═C                                                                            S    --(CH.sub.2).sub.3 --                      212   CH.sub.3                                                                          NH.sub.2                                                                           tBut                                                                              F   H  Me CH.sub.2 --N                                                                        NH   --CH.sub.2 --CH═CH--CH.sub.2 --        213   iProp                                                                             NH.sub.2                                                                           nProp                                                                             CN  tBut                                                                              Me CH.sub.2 --N                                                                        S    --CH.sub.2 --CH═CH--CH.sub.2 --        214   CH.sub.3                                                                          OH  nProp                                                                             C═CH                                                                           tBut                                                                              OMe                                                                               CH═C                                                                            --CH.sub.2 --                                                                       --CH.sub.2 --C(CH.sub.3)═CH--CH.su                                         b.2 --                                     215   iProp                                                                             NHMe                                                                               tBut                                                                              CN  H  OMe                                                                               CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.4 --                      216   CH.sub.3                                                                          OH  H  H   iProp                                                                             OMe                                                                               CH.sub.2 --N                                                                        S    --(CH.sub.2).sub.3 --                      __________________________________________________________________________

Examples of Pharmaceutical Forms

    ______________________________________                                         Tablets of the following composition are compressed                            in a tabletting machine in a conventional manner:                              ______________________________________                                         A) Tablets                                                                     40     mg      of substance of Example 1                                       120    mg      of corn starch                                                  13.5   mg      of gelatin                                                      45     mg      of lactose                                                      2.25   mg      of Aerosil ® (chemically pure silica in sub-                               microscopically fine dispersion)                                6.75   mg      of potato starch (as 6% strength paste)                         B) Sugar-coated tablets                                                        20     mg      of substance of Example 4                                       60     mg      of core composition                                             70     mg      of sugar-coating composition                                    ______________________________________                                    

The core composition comprises 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer. The sugar-coating composition comprises 5 parts of sucrose, parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets produced in this way are subsequently provided with an enteric coating.

Biological Investigations--Receptor-Binding Studies

1) D₃ binding assay

Cloned human D₃ receptor-expressing CCL 1.3 mouse fibroblasts obtained from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were used for the binding studies.

Cell Preparation

The D₃ -expressing cells were grown in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U/ml penicillin and 0.2% Streptomycin (GIBCO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization with medium was then carried out, and the cells were collected by centrifugation at 300×g. To lyze the cells, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4, with 10% glycerol) and then incubated in a concentration of 10⁷ cells/ml of lysis buffer at 4° C. for 30 min. The cells were centrifuged at 200×g for 10 min and the pellet was stored in liquid nitrogen.

Binding Assays

For the D₃ receptor-binding assay, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4, with 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA) in a concentration of about 10⁶ cells/250 μl of assay mixture and incubated at 30° C. with 0.1 nM ¹²⁵ iodosulpiride in the presence and absence of test substance. The non-specific binding was determined using 10⁻⁶ M spiperone.

After 60 min, the free and the bound radioligand was separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway), and the filters were washed with ice-cold tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by non-linear regression analysis using the LIGAND program.

2) D₂ Binding Assay

Membrane Preparation

a) Nucleus Caudatus (Bovine)

Nucleus caudatus was removed from bovine brain and washed with ice-cold 0.32 M sucrose solution. After determination of the weight, the material was comminuted and homogenized in 5-10 volumes of sucrose solution using a Potter-Evehjem homogenizer (500 rpm). The homogenate was centrifuged at 3,000×g for 15 minutes (4° C.), and the resulting supernatant was subjected to another 15-minute centrifugation at 40,000×g. The residue was then washed twice, by resuspension and centrifugation, with 50 mM tris-HCl, pH 7.4. The membranes were stored in liquid nitrogen until used.

b) Striatum (Rat)

Striati from Sprague-Dawley rats were washed in ice-cold 0.32 M sucrose solution. After determination of the weight, the parts of the brain were homogenized in 5-10 volumes of sucrose solution using a Potter-Elvehjem homogenizer (500 rpm). The homogenate was centrifuged at 40,000×g for 10 minutes (4° C.), and then the residue was washed several times, by resuspension and centrifugation, with 50 mM tris-HCl, 0.1 mM EDTA and 0.01% ascorbic acid (pH 7.4). The washed residue was resuspended in the abovementioned buffer and incubated at 37° C. for 20 minutes (to break down the endogenous dopamine). The membranes were then washed twice with buffer and portions were frozen in liquid nitrogen. The membrane preparation was stable for a maximum of one week.

Binding Assay

a) ³ H-Spiperone (D_(2low))

Nucleus caudatus membranes were taken up in incubation buffer (mM: tris-HCl 50, NaCl 120, KCl 5, MgCl₂ 1, CaCl₂ 2, pH 7.4). Various mixtures, each of 1 ml, were prepared:

Total binding: 400 μg of membranes+0.2 nmol/1 ³ H-spiperone (Du Pont de Nemours, NET-565).

Non-specific binding: as mixtures for total binding+10 μM (+)-butaclamol.

Test substance: as mixtures for total binding+increasing concentrations of test substance.

After incubation at 25° C. for 60 minutes, the mixtures were filtered through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector (from Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by non-linear regression analysis using the LIGAND program or by conversion of the IC₅₀ values using the formula of Cheng and Prusoff.

b) ³ H-ADTN (D_(2high))

Striatum membranes were taken up in incubation buffer (50 nM tris-HCl, pH 7.4, 1 mM MnCl₂ and 0.1% ascorbic acid).

Various mixtures, each of 1 ml, were prepared.

Total binding: 300 μg wet weight+1 nM ³ H-ADTN (Du Pont de Nemours, customer synthesis)+100 nM SCH 23390 (occupation of D1 receptors).

Non-specific binding: as mixtures for total binding+50 nM spiperone.

Test substance: as mixtures for total binding+increasing concentrations of test substance.

After incubation at 25° C. for 60 minutes, the mixtures were filtered through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector (from Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The evaluation took place as under a).

In these assays, the compounds according to the invention show very good affinities and high selectivities for the D₃ receptor. The results obtained for representative compounds are compiled in the following Table 9.

                  TABLE 9                                                          ______________________________________                                         Receptor binding                                                                        D.sub.3       D.sub.2                                                 Example  .sup.125 I-sulpiride                                                                         .sup.3 H-spiperone                                                                       Selectivity                                   No.      K.sub.i [nM]  K.sub.i [mM]                                                                             K.sub.i D.sub.2 /K.sub.i D.sub.3              ______________________________________                                         10       4.5           219       49                                            15       8.8           517       58                                            24       1.8           120       67                                            41       8.1           1,500     185                                           42       13.4          2,450     182                                           37       1.7           300       176                                           ______________________________________                                    

For comparison, the compound of the formula ##STR33## (U.S. Pat. No. 4,577,020; Example 3) was subjected to the above D₃ binding assay. A K_(i) of 4100 [nM] was found; ie. the compound has virtually no affinity for the D₃ receptor. 

We claim:
 1. A triazole compound of the formula I ##STR34## where A is a straight-chain or branched C₁ -C₁₈ -alkylene group, or a straight-chain or branched group consisting of 1 to 18 methylene members and one or two members selected from the group consisting of O, S, NR³, NR³ CO, COO, OCO, C₃ -C₆ -cycloalkylene, a double bond and a triple bond,X is a radical of the formula ##STR35## R¹ is H, CO₂ R³, NR³ R⁴, OR⁴, C₃ -C₆ -cycloalkyl or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen; R² has the meanings indicated for R¹ or is CF₃, SR³, halogen or CN; R³ is H or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl, phenyl or halogen; R⁴ has the meanings indicated for R³ or is COR³ or CO₂ R³ ; Ar is 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl or 6-pyrimidyl, where Ar may carry from one to four substituents selected from the group consisting of OR⁴, C₁ -C₈ -alkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, halogen, CN, CO₂ R³, NO₂, SO₂ R³, SO₃ R³, NR³ R⁴, SO₂ NR³ R⁴, SR³, CF₃, CHF₂, C₃ -C₆ -cycloalkyl and phenyl, where the carbocyclic ring may be unsubstituted or substituted by C₁ -C₈ -alkyl, halogen, OC₁ -C₈ -alkyl, OH, NO₂ or CF₃ andor a salt thereof with physiologically tolerated acid.
 2. The compound of the formula I as defined in claim 1 whereR¹ is H, CO₂ R³, NR³ R⁴, OR⁴ or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen; R³ is H or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen; Ar is 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl or 6-pyrimidyl, where Ar may carry one or two substituents selected from the group consisting of OR⁴, C₁ -C₈ -alkyl, halogen, CN, CO₂ R³, NO₂, SO₂ R³, SO₃ R³, NR³ R⁴, SO₂ NR³ R⁴, SR³, CF₃, CHF₂, C₃ -C₆ -cycloalkyl and phenyl, where the carbocyclic ring may be unsubstituted or substituted by C₁ -C₈ -alkyl, halogen, OC₁ -C₈ -alkyl, OH, NO₂ or CF₃.
 3. The compound of the formula I as defined in claim 1 where A is C₁ -C₁₀ -alkylene, or is a group consisting of 1 to 18 methylene members and one or two members selected from the group consisting of O, S, NR³, cyclohexylene, a double bond and a triple bond.
 4. The compound of the formula I as defined in claim 1 whereR¹ is H or OR⁴, where R⁴ is H, C₃ -C₆ -cycloalkyl or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen; R² is H, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or NR³ R⁴, where R³ and R⁴ are, independently of one another, H, phenyl-C₁ -C₈ -alkyl or C₁ -C₈ -alkyl, or OR⁴ where R⁴ is H or C₁ -C₈ -alkyl, or CF₃ ; and Ar is 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl or 6-pyrimidyl, where Ar may carry one, two, three or four substituents selected from the group consisting of C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or OR⁴ where R⁴ is H, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or CHF₂, CF₃, CN, halogen, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, C₃ -C₆ -cycloalkyl or phenyl.
 5. The compound of the formula I as defined in claim 1 whereAr is 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl or 6-pyrimidyl, which may carry one to three substituents selected from the group consisting of C₁ -C₈ -alkyl, phenyl, C₃ -C₆ -cycloalkyl, OH, OC₁ -C₈ -alkyl, halogen, CN, CF₃ and CHF₂ ; R¹ is H or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, R² is H, NR³ R⁴ or OR⁴ where R³ and R⁴ are, independently of one another, H, C₁ -C₈ -alkyl or phenyl-C₁ -C₈ -alkyl; A is C₁ -C₁₀ -alkylene, or is a group consisting of 1 to 10 methylene members and one or two members selected from the group consisting of O, S, NR³ where R³ is H or C₁ -C₈ -alkyl, a double bond and a triple bond.
 6. A pharmaceutical composition containing a compound of the formula I as defined in claim 1, and a conventional pharmaceutical aid.
 7. A method for treating a disorder which responds to dopamine D₃ receptor ligands, wherein an effective amount of a compound of the Formula I as defined in claim 1 is administered to a person requiring such treatment.
 8. A compound of the formula I as defined in claim 1, wherein A is S--CH₂ --CH₂ --CH₂, the S-atom being bonded to the triazole ring, R¹ is methyl, R² is NH₂, and Ar denotes 2-tert-butyl, 6-trifluoromethyl-pyrimidin-4-yl.
 9. The method of claim 7, wherein the disorder which responds to dopamine D₃ receptor ligands is schizophrenia, depression, a neurosis or a psychosis. 